Human-to-human transmission of variola virus occurs by inhalation of large, virus-containing airborne droplets of saliva from an infected person. Infectious virus particles are released from the sloughing off of oropharyngeal lesions. Smallpox patients are considered infectious from the time the first oropharyngeal lesions appear, throughout the course of the disease, until the last scab falls off the body.

A person is considered at risk for contracting smallpox after prolonged, close contact with an infectious smallpox patient. Before smallpox was eradicated, the disease had a secondary household or close contact attack rate of approximately 60% among unvaccinated individuals.

Transmission via contact with material from the smallpox pustules or crusted scabs can also occur. Scabs are much less infectious than respiratory secretions, though, presumably due to binding of the virions in the fibrin matrix of the scab.

Though rare, there have also been reports of airborne transmission in hospital and laboratory settings. Adhering to infection control procedures can reduce this risk. There are no known animal or insect reservoirs of smallpox.